As malaria continues to remain a major public health challenge in much of the world, the loss of effective and affordable antimalarials through resistance development in malaria parasites is a continuing grave concern. With the parasite genome sequence at hand, there is a renewed hope that a reasonable drug pipeline can be established for dealing with these challenges. A critical goal of basic molecular and cell biological research on malaria parasites is to explore appropriate targets for developing new antimalarials. Our group has previously identified and validated the parasite mitochondrion as an attractive target for antimalarial drugs. Mechanisms of action and resistance to one of the currently used drugs, atovaquone, were elucidated by work in this group. A new class of compounds being developed also appears to target mitochondrial physiology in malaria parasites with related but distinct mode of action from that for atovaquone. One of the aims for the renewed project will be to investigate this series of compounds to derive useful mechanistic details that could aid in further drug development. Biochemical and genomic insights provided by recent work suggest that the parasite mitochondrion is physiologically quite distinct from its host's organelle. For the renewed project, a series of approaches will be taken to understand roles played by some of the canonical mitochondrial processes in different stages of malaria parasite life cycle. Through improved gene disruption methods, some of the questions of long standing regarding the role of the mitochondrion in malaria parasite biology will be addressed. A surprising finding has been the ability of malaria parasites to survive for significant length of time even with inhibited mitochondrial electron transport and collapsed mitochondrial membrane electropotential. Work to be conducted in the renewed project will address mechanisms by which parasites are killed by anti-mitochondrial drugs. Overall, research to be conducted during the next funding period will aim to advance the underlying goals of this project: to derive a deeper understanding of the functional significance the mitochondrion in malaria parasites and the mechanisms by which interference with the mitochondrial functioning leads to parasite demise.